Exploiting time-of-flight in photon cascade emissions for direct imaging of therapeutic radionuclides

The National Institute of Biomedical Imaging and Bioengineering awarded The Regents of the University of California, operating Lawrence Berkeley National Laboratory, $312,165 on June 1, 2026, under the Discovery and Applied Research for Technological Innovations to Improve Human Health program (CFDA 93.286) to develop Time-of-Flight Multi-Photon Emission Tomography (TOF-MPET) for direct imaging of therapeutic radionuclides in cancer treatment.

The project addresses limitations in current imaging modalities for radiopharmaceutical therapies (RPT). Existing SPECT technology lacks sufficient sensitivity to image alpha therapy radiopharmaceuticals, which are administered at very low activities (0.1–1 millicurie), orders of magnitude lower than conventional nuclear imaging protocols. TOF-MPET exploits subnanosecond gamma-cascade emissions from RPT radionuclides, including the top candidates for therapeutic use, to dramatically improve signal-to-noise ratio and sensitivity compared to SPECT. The technique applies coincidence detection and time-of-flight measurement to lower the minimum imageable activity threshold and produce accurate images for theranostic approaches—where imaging informs treatment planning to improve patient response in targeted radiopharmaceutical therapy.

Work is performed in Berkeley, California. The award runs from June 1, 2026, through April 30, 2028. The assistance type is a Project Grant, which provides hypothesis- and technology-driven research support under NIBIB's mission to advance biomedical imaging and bioengineering technologies.

Abstract

(ABSTRACT) radiopharmaceutical therapies (RPT) are extremely promising for cancer treatment. RPT is a rapidly growing treatment modality that has demonstrated a great success in the treatment and care of multiple malignancies. The efficacy of rpts relies on delivering a very targeted radiation dose to tumor cells, sparing healthy tissue. Using imaging to inform RPT treatment, known as theranostics (therapy + diagnostic), has shown a superior patient response than the regular one-size-fits-all approach for beta therapy with 177LU and 131I. However, spect technology is very limited when IT comes to imaging of alpha therapy radiopharmaceuticals since they are injected at very low activities (0.1-1 MCI), orders of magnitude lower than for 99MTC spect (1-10 MCI) or beta therapy (~100MCI). The typical spect sensitivity of 0.01% is not enough to precisely image alpha rpts. On the other hand, time-of-flight positron emission tomography has emerged as the standard of care for a number of types of malignancies due to its superb image quality. However, IT requires positron emitters, so IT cannot be applied to the most popular RPT radionuclides presented above since they do not emit positrons. There is a need for an imaging modality capable of lowering the minimum imageable activities (MIA) and to obtain accurate images of rpts. Thus, we propose a completely novel nuclear imaging modality (time-of-flight multi-photon emission tomography or TOF-mpet) that relies on emission of subnanosecond gamma-cascades to dramatically improve signal-to-noise ratio (SNR) and sensitivity to RPT radionuclides with respect to spect. All the top candidates for rpts mentioned above present subnanosecond gamma-cascades, which allows to exploit coincidence detection and TOF to improve imaging of those RPT radionuclides. This technique can be also extended to other non-rpts that present such photon cascades. This project aims to set the technical ground for TOF-mpet and to provide a demonstration of its performance with a minimal system. We envisioned two ways of exploiting TOF in gamma-cascade emitters: with and without a collimator. With a collimator, TOF-mpet uses TOF to provide depth perception and to form 3D images with a single detector view, resulting in an enhanced SNR. The rationale behind this technology is similar to the one that led from pet to TOF-pet. Without a collimator, TOF-mpet dramatically increases the sensitivity, as well as eliminating the trade-off between sensitivity and resolution introduced by the use of collimators. Our specific aims are (aim 1) to demonstrate that collimated TOF-mpet can substantially improve SNR relative to spect and (aim 2) to demonstrate that uncollimated TOF-mpet can dramatically lower the MIA.